Avian influenza viruses pose a significant threat to public health due to their associations with influenza pandemics. The outbreaks of the highly pathogenic H5N1 chicken influenza in Asia in 1997 and 2003-4 are characterized by the high mortality among the infected individuals. Development of an effective H5N1 vaccine is hampered by the poor immunogenicity of all vaccine candidates tested in humans to date. Although the mechanism of the poor immunogenicity is unclear, lack of priming with H5 virus in humans has been speculated to play a major role. Genetically modified H5 hemagglutinin (HA) with depletion of the virulent polybasic structure at its cleavage site has previously been shown to be a potential vaccine candidate mimicking the antigenicity of the wild type (wt) H5N1 viruses. However, the possibility of reversion of the virulent structure is of great concern. The objective of this project is to improve the safety and immunogenicity of H5 vaccine through genetic engineering. Our unique approach for the development of a safe and effective H5 vaccine is based on using chimeras containing B-cell epitopes of H5 influenza virus and T-cell epitopes derived from H3 and H1 subtype human influenza viruses. The chimeric approach may have the potential of improving the anti-H5 antibody response, as it contains T-helper epitopes that are already primed in human population and therefore could facilitate the production of neutralizing antibodies. Furthermore, the chimeric approach may also improve the safety profile of recombinant H5 vaccine. The Phase I study is aimed to demonstrate the viability of the chimeras using reverse genetics, and to conduct analysis on antigenicity, growth property, and immunogenicity in mice. The Specific Aims are to: 1) construct and rescue the human-avian virus chimeras. 2) evaluate the safety and immunogenicity in mice.